Recent advances and remaining challenges in lung cancer therapy

Abstract

Lung cancer remains the most common cause of cancer death. Given the continued research into new drugs and combination therapies, outcomes in lung cancer have been improved, and clinical benefits have been expanded to a broader patient population. However, the overall cure and survival rates for lung cancer patients remain low, especially in metastatic cases. Among the available lung cancer treatment options, such as surgery, radiation therapy, chemotherapy, targeted therapies, and alternative therapies, immunotherapy has shown to be the most promising. The exponential progress in immuno-oncology research and recent advancements made in the field of immunotherapy will further increase the survival and quality of life for lung cancer patients. Substantial progress has been made in targeted therapies using tyrosine kinase inhibitors and monoclonal antibody immune checkpoint inhibitors with many US Food And Drug Administration (FDA)-approved drugs targeting the programmed cell death ligand-1 protein (e.g., durvalumab, atezolizumab), the programmed cell death-1 receptor (e.g., nivolumab, pembrolizumab), and cytotoxic T-lymphocyte-associated antigen 4 (e.g., tremelimumab, ipilimumab). Cytokines, cancer vaccines, adoptive T cell therapies, and Natural killer cell mono- and combinational therapies are rapidly being studied, yet to date, there are currently none that are FDA-approved for the treatment of lung cancer. In this review, we discuss the current lung cancer therapies with an emphasis on immunotherapy, including the challenges for future research and clinical applications.

Introduction

In the past decade, for the first time, there has been a decrease in the incidence of lung cancer, with the incidence in women decreasing at only about half the rate of men (1.1% vs. 2.6% annually).^[1] However, with an estimated 1.8 million deaths each year worldwide, lung cancer remains the leading cause of cancer death, accounting for 18% of cancer deaths.^[2] As of 2023, lung cancer is predicted to account for 238,340 new cases and 127,070 deaths in the United States alone.^[1] Contributing to 85% of the histological types of lung cancer, non-small cell lung carcinoma (NSCLC) encompasses lung adenocarcinoma (40% of all lung cancers), squamous cell carcinoma (30% of all lung cancers), large cell (undifferentiated) carcinoma (15% of all lung cancers), and other rare mixed histotypes such as adenosquamous carcinoma and sarcomatoid carcinoma.^[3] On the other hand, ~15% of all lung cancers are classified as small cell lung cancer (SCLC), also referred to as oat cell cancer, which grows and spreads faster than NSCLC.

Different kinds of cancer treatment approaches have been developed to fight lung cancer with the most common being systemic chemotherapy, especially platinum-based agents, in combination with radiotherapy and surgery for tumor resection.^[4,5] Over the past few decades, rapid diagnosis and standard treatment progression have not yielded significant survival benefits; the 5-year survival rate for lung cancer in most countries is less than 30%.^[6] Considerable improvements have been made in the targeted therapies against molecular alterations during malignancy. Clinical trials that target oncogenic mutations of anaplastic lymphoma kinase (ALK) and epidermal growth factor receptor (EGFR) via tyrosine kinase inhibitors (TKIs) have shown improved quality of life and response rate in patients with lung cancer.^[7,8]

Immunotherapies alone or in combination with targeted therapies may be the ultimate curative option. The representative immunotherapy for lung cancer is monoclonal antibodies targeting immune checkpoints. Cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) and programmed cell death-1 (PD-1) are two of the most widely studied immune-checkpoint receptors for lung cancer therapy. However, a vast majority of patients are refractory to checkpoint blockade and its efficacy depends critically on the presence of sufficient tumor-specific lymphocytes.^[9] Adoptive cell therapies (ACTs) are in clinical trials with promising results, but many hurdles still exist, especially for chimeric antigen receptor (CAR)-T cell therapy.^[10] Other groups have focused on reviewing the molecular^[11] and tumor heterogeneity^[12], epidemiology,^[13] biomarkers as diagnostic tools,^[14] targeted treatments,^[15] CAR-T cell therapy challenges,^[16] and more recently first-line immunotherapies for lung cancer.^[17,18,19] In this review, we provide a comprehensive overview of the current therapies with an emphasis on immunotherapies against lung cancer, specifically the most recent progress of adoptive cell therapies and challenges for future research and cell therapy applications.

Current Standards of Treatment for Lung Cancer

The first line of treatment for different lung cancer histotypes varies according to age, regions affected, extent of disease, tolerance to medication, and patient preference. Treatment options include surgery, radiation, chemotherapy, targeted therapy, immunotherapy, or a combination of treatments. For NSCLC, the first line of treatment is often surgery to remove the tumor. For larger tumors or those that have spread to nearby lymph nodes, a combination of surgery, chemotherapy, and radiation therapy may be recommended. As for SCLC, the first line of treatment is typically chemotherapy and radiation therapy. Surgery may be an option for early-stage SCLC, but it is not usually recommended for advanced cases.

Targeted therapy with TKIs is another current standard of lung cancer treatment. A well-established molecular target for lung cancer is EGFR, a receptor tyrosine kinase also known as ErbB1/human epidermal growth factor receptor 1 (HER1) included in the ErbB family of tyrosine kinase receptors which also comprise ErbB2/human epidermal growth factor receptor 2 (HER2)/Neu, ErbB3/human epidermal growth factor receptor 3 (HER3), and ErbB4/human epidermal growth factor receptor 4 (HER4).^[20] EGFR activates many cellular signaling pathways that regulate growth, proliferation, and survival, and as the ERBB1 (EGFR) gene mutation was the first discovered mutation in NSCLC patients, it is the most common target of targeted therapy, which is characterized by 20% of patients with lung adenocarcinoma. First-generation TKIs, including gefitinib, icotinib, and erlotinib, which cause a reversible blockade of ATP-binding sites thereby stopping downstream signaling, have shown better responses and improved survival compared to cytotoxic therapy in previously untreated patients with EGFR mutations. Second-generation EGFR TKIs include afatinib and dacomitinib, which are irreversible inhibitors that also target HER2 and HER4 and provide an alternative for patients who acquired resistance to first-generation TKIs. Both afatinib and dacomitinib showed improved survival compared to gefitinib. The third-generation TKIs, such as osimertinib, rociletinib, olmutinib, and lazertinib, presented a new treatment option for patients with T790M EGFR-mutant tumors, which is the most common mechanism of resistance in patients who receive first- and second-generation TKIs. The ALK gene encodes a tyrosine kinase receptor that shares a high level of similarity with the insulin receptor but with a unique glycine-rich extracellular domain. Crizotinib is an oral competitive ATP inhibitor of ALK, MET, and ROS1 tyrosine kinases with activity against ALK fusion-positive NSCLC. Second-line and third-line treatment for NSCLC depends on the gene mutations found in the tumor resulting from the treatments that patients have already received.^[21] More therapeutic options will be available for NSCLC patients with rare genetic aberrations and molecular alterations, mutations, and rearrangements including BRAF, KRAS, NTRK, and RET. New therapeutic targets in NSCLC are being evaluated in ongoing clinical trials and their efficacy has been recently reviewed.^[22]

Immunotherapy for Lung Cancer

Among the strategies against lung cancer, the most promising are immunotherapies which include (1) non-specific immunotherapies such as cytokines, (2) monoclonal antibodies (mAbs) and immune checkpoint inhibitors, (3) oncolytic virus therapy, (4) cancer vaccines, and (5) adoptive cell therapy (e.g., T cells and natural killer [NK] cells), alone or in combination with other therapeutic agents [Figure 1].

Figure 1.

Immunotherapy types for lung cancer. ADCC: Antibody-dependent cell-mediated cytotoxicity; ADCP: Antibody-dependent cell mediated phagocytosis; CTLA-4: Cytotoxic T-lymphocyte-associated antigen 4; GzmB: Granzyme B; IL: Interleukin; MHC: Major histocompatibility complex; NF-κB: Nuclear factor-κB; NK: Natural killer; PD-1: Programmed cell death-1; PD-L1: Programmed cell death ligand-1; PRF: Platelet-rich fibrin; TCR: T cell receptor.

Non-specific immunotherapies

Toll-like receptor (TLR), a pattern recognition receptor (PRR) that recognizes pathogen-associated molecular patterns (PAMPs) to induce antigen-specific innate immunity, agonists have been investigated for their ability to enhance anti-tumor immune responses.^[23] TLR9 is expressed by human B cells and plasmacytoid dendritic cells (pDCs). Synthetic unmethylated 5′–C–phosphate–G–3′ (CpG) oligodeoxynucleotides (CpG ODN) can activate TLR9 to reduce immune tolerance and promote anti-tumor response. Two Phase III trials evaluated TLR9 agonist PF-3512676 in combination with first-line paclitaxel/carboplatin^[24] and gemcitabine/cisplatin^[25], respectively, in advanced NSCLC; however, both studies were terminated due to lack of efficacy and increased toxicity. Other TLR9 agonists, such as IMO-2055^[26] and MGN1703^[27], are still in early development. The anti-tumor potential for TLR7 agonists has also been shown in pre-clinical studies via activation of pDCs, whereas TLR7 expression on lung cancer cells and its stimulation by TLR7 agonists promote tumor progression and resistance to chemotherapy.^[28] Finally, TLR3 agonists can enhance tumor-specific T-cell responses and are currently being used as adjuvants for cancer vaccines in preclinical models.^[29]

The use of cytokines is another emerging form of immunotherapy against lung cancer. Mammalian actin-binding protein-1 (MABP1) is a human monoclonal antibody that targets interleukin (IL)-1α. In a Phase I study, 16 patients with NSCLC who were refractory to the standard chemotherapy were given MABP1 in a dose-escalating manner.^[30] The median overall survival (OS) was 7.6 months, and the median progression-free survival (PFS) was 57 days. Interestingly, there was a correlation between the patients with anti-EGFR pretreatment prior to MABP1 treatment and a better treatment outcome.^[30] Median OS in the anti-EGFR pretreated patients was 9.4 months, versus non-pretreated patients with a median OS of 4.8 months. Median PFS was also higher in the anti-EGFR pretreated group than non-pretreated group (97 days and 78 days, respectively). The sample size was small, and the study was underpowered to be conclusive. Nevertheless, given the relative success in the anti-EGFR pretreatment group, the relationship of EGFR, IL-1α, and NSCLC should be an area of continued study, especially considering the encouraging results from MABP1 in the treatment of colorectal cancer.

The efficacy of IL-2 treatment in patients with NSCLC remains questionable. In a Phase III study, 239 patients with stage IIIb or IV NSCLC were randomly assigned to receive either gemcitabine + cisplatin (chemotherapy only), or gemcitabine + cisplatin + IL-2 (chemotherapy + IL-2). The median OS and median PFS were 10.5 and 6.6 months, respectively, in the chemotherapy + IL-2 arm and 12 and 6.9 months, respectively, in the chemotherapy only arm. The statistical differences of these two groups were nonsignificant in both OS and PFS.^[31] Yet, in a separate Phase I/II trial, 45 patients with stage III NSCLC were studied. Thirteen patients received gemcitabine, cisplatin, and recombinant IL-2 (rIL-2), followed by surgery (chemotherapy + IL-2 + surgery). The remaining 32 patients received gemcitabine, cisplatin, and surgery (chemotherapy + surgery). The 5-year OS rate in the chemotherapy + IL-2 + surgery group was 59% compared to the group without rIL-2 therapy at 32%.^[32] A striking 66% reduction in the hazard of death was observed in patients receiving rIL-2 immunotherapy. Despite this, no significant difference was found between the two groups in OS and event-free survival (EFS). Overall, further research is warranted to determine the efficacy of IL-2 immunotherapy treatment in patients with NSCLC.

In a first-in-Human Phase I study of subcutaneous outpatient recombinant human IL15 (rhIL15), E. coli-derived rhIL-15 was subcutaneously administered to patients with melanoma, renal cell carcinoma, squamous cell head and neck carcinoma, and NSCLC, in which the maximum tolerated dose of IL-15 administered subcutaneously was significantly higher than the dose that was feasible by intravenous bolus injection, and reached 3.0 μg/kg per day.^[33] In another study, the number of circulating NK cells dramatically increased with IL-15 administration in a dose-dependent fashion. ALT-803, a superagonist complex of an IL-15 mutein bound to the sushi domain of IL-15Rα fused to the immunoglobulin G1 Fc, in combination with nivolumab (anti-PD-1 mAb) may repeatedly elicit objective responses to anti-PD-1 immunotherapy after relapse or treatment failure in patients with NSCLC.^[34] Finally, the roles of IL-12, IL-21, as well as interferons in the treatment of lung cancer have not been fully explored.

Talactoferrin alfa, a recombinant human lactoferrin, is an orally active dendritic cell-mediated immunotherapy thought to interact with DCs in the gut wall leading to the production of an immunostimulatory cytokine cascade, thereby stimulating the migration and maturation of tumor antigen-presenting DCs.^[35] Despite demonstrating anti-tumor activity in a variety of different pre-clinical models, these findings were not validated in an international randomized Phase III trial referred to as the FORTIS-M study in patients with advanced NSCLC, and therefore further testing came to a halt.^[36]

Monoclonal antibodies

mAbs are proteins that are designed to target specific proteins on the surface of cancer cells. These mAbs can be used to either block the signals that cancer cells use to grow and divide or to mark the cancer cells for recognition and destruction by the immune system. A critical part of the immune system is to keep itself from attacking normal cells, and therefore the body uses “checkpoint” proteins on immune cells to turn on/off an immune response. Cancer cells can develop strategies to use these checkpoints to evade the immune system, which can then be targeted by drugs called immune checkpoint inhibitors (ICIs). ICIs have been largely used for NSCLC treatment.

Targeting ICIs, such as CTLA-4, PD-1, and PD-L1, has demonstrated promising clinical efficacy and durable responses in a broad spectrum of cancers, including lung cancer. PD-1 and PD-L1 targeted immunotherapy drugs that have been approved to treat NSCLC include atezolizumab (Tecentriq) and durvalumab (Imfinzi) which target PD-L1, and nivolumab (Opdivo), pembrolizumab (Keytruda), and cemiplimab (Libtayo) which target PD-1.^[37] CTLA-4 (or CD152) is expressed on T lymphocytes, and competes with CD28, which is a co-stimulatory receptor on T lymphocytes, by binding with B7 (CD80 or CD86) on antigen-presenting cells (APCs) with higher affinity and avidity. An inhibitory signal is generated when CTLA-4 binds with B7 on activated T cells. Drugs that block the CTLA-4 pathway include ipilimumab (Yervoy), a human IgG1 mAb, which is given in combination with nivolumab (Opdivo), and sometimes in combination with chemotherapy. Tremelimumab is another human IgG2 mAb directed at CTLA-4. Durvalumab is also frequently combined with tremelimumab for dual checkpoint inhibitor studies in NSCLC.

The combination of immune checkpoint blockade and chemotherapy produces a synergized effect to confer better survival outcomes. Chemotherapy is the first choice for patients who lack targetable driver mutations. Pembrolizumab targeting PD-1 was combined with chemotherapy in several clinical trials (KEYNOTE-021,^[38] KEYNOTE-189,^[39] and KEYNOTE 407^[40]). In 2018, the combination of pembrolizumab with pemetrexed and carboplatin was approved as a first-line treatment for metastatic NSCLC patients with no driver mutation, irrespective of PD-L1 expression based on the results shown by KEYNOTE-021. A subsequent Phase III trial concluded that the addition of pembrolizumab to chemotherapy resulted in a significantly longer OS and PFS than chemotherapy alone (KEYNOTE-189).^[39] Later, an expanded approval was obtained for the combination of pembrolizumab with carboplatin and paclitaxel/nab-paclitaxel (Abraxane) for metastatic squamous NSCLC, irrespective of PD-L1 expression (Keynote-407). In 2018, the efficacy of nivolumab in combination with ipilimumab, an ICI targeting CTLA-4, was first demonstrated in a Phase I trial (CheckMate 012) as a first-line treatment of advanced NSCLC with a tolerable safety profile and a high and durable response.^[41] Durvalumab was also combined with osimertinib (a third-generation EGFR-TKI) in a Phase III trial (CAURAL); however, the clinical trial was terminated early because of an increased incidence of interstitial lung disease-like events. In the CheckMate 012 trial, nivolumab combined with erlotinib was tolerable in patients with EGFR-mutated advanced NSCLC.^[42]

Antibody-drug conjugates (ADCs) are a novel class of biopharmaceutical drugs in which a monoclonal antibody is linked to a cytotoxic drug. Traztuzumab deruxtecan (T-DXd), which consists of trastuzumab and the payload deruxtecan, a topoisomerase I inhibitor, is the first ADC approved for patients with HER2 mutation-positive NSCLC.^[43] Two other ADCs (patritumab deruxtecan,^[44] and telisotuzumab vedotin^[45]) have been granted U.S. Food and Drug Administration (FDA) Breakthrough Therapy Designation and are currently under evaluation. Moreover, novel ADCs targeting HER2,^[46] HER3,^[47] Trop-2,^[48,49] and c-Met,^[50] either as monotherapy or in combination strategies are being clinically evaluated in lung cancer.

Considering many patients experience lung tumor recurrence within five years following surgery, studies have focused on perioperative regimens that combine immunotherapy with chemotherapy. The AEGEAN clinical trial assessed the activity of durvalumab, a human IgG1 mAb targeting PD-L1, alone or in combination with platinum-based chemotherapy prior to surgery. Findings revealed perioperative immunotherapy in resectable NSCLC demonstrated improved pathologic complete response and event-free survival in patients without prior treatment, and perioperative durvalumab plus neoadjuvant chemotherapy was associated with significantly greater event-free survival and pathological complete response than neoadjuvant chemotherapy alone.^[51] The same study was repeated but not as effective when pembrolizumab was used.^[52] Further studies are required to find appropriate target patients that may benefit from mAb combinational therapies.

Oncolytic virus therapy

There are currently 14 clinical trials of lung cancer-associated oncolytic viruses.^[53] Oncolytic viruses are designed to preferentially infect and replicate in tumors, which not only promotes cell death but also enhances immune mediators entering the tumor microenvironment and induces systemic anti-tumor immunity. Phase 1 study of intravenous administration of the chimeric adenovirus enadenotucirev in patients undergoing primary tumor resection (previously known as ColoAd1), a tumor-selective chimeric adenovirus, stimulated local high anti-tumor immune response and the infiltration of CD8⁺ T cells in NSCLC.^[54] Furthermore, using oncolytic adenovirus or vaccinia virus-infected reprogrammed somatic-derived tumor cell vaccine (VIReST) regimen to vaccinate high-risk populations can prevent tumor progression and initiate long-term anti-tumor immune response, which can be used in the treatment and prevention of lung cancer. Myxoma virus (MYXV) is a distinct Leporipoxvirus initially identified as the causative agent for myxomatosis, a lethal disease specific to European rabbit strains (Oryctolagus cuniculus) but nonpathogenic for other mammals. A rabbit-specific poxvirus, MYXV, is able to infect and replicate in tumor cells derived from diverse species, and oncolytic activity has been demonstrated for several human tumor lineages. Kellish et al^[55] selected human SCLC as a solid tumor model for preclinical testing for MYXV therapy. “Oncolytic therapeutic vaccine” is a combination strategy utilizing oncolytic virus encoding one or more tumor-associated antigens or neoantigens.

Cancer vaccines

The normal lung environment is constantly exposed to foreign antigens, including inanimate dust, viruses, bacteria, and fungi. Imbalances in immune activation and immune suppression can lead to autoimmune diseases such as asthma or interstitial lung disease. Generating vaccines to target lung cancer requires fine-tuning immune activation. There are protein and peptide vaccines (MAGE-A3, L-BLP25) as well as cell-based vaccines (GVAX, Belagenpumatucel-L) targeting lung cancer.

NSCLC patients whose tumors express the tumor-associated antigen (TAA) melanoma associated antigen-A3 (MAGE-A3) are often associated with poorer prognosis. The MAGE-A3 vaccine is a recombinant MAGE-A3 protein combined with the immunostimulant AS02B that was assessed in a large, double-blind, randomized Phase III trial (MAGRIT) in patients with stage IB, II, or IIIA MAGE-A3-positive NSCLC. Unfortunately, this study found no overt increase in disease-free survival in the vaccine group compared with placebo in either the overall population or in the patients who did not receive chemotherapy, and further development of the MAGE-A3 immunotherapy for NSCLC patient use has been stopped.

TG4010 is a vaccine targeted against Mucin1 (MUC1) antigen composed of a recombinant vaccinia virus (modified virus of Ankara or MVA) that encodes human MUC1 and IL-2 (MVA-MUC1-IL-2).^[56] Belagenpumatucel-L is an allogeneic tumor cell vaccine containing four irradiated NSCLC cell lines and an antisense plasmid of tranforming growth factor-β (TGF-β).^[57] The vaccine aims to increase the immune response to NSCLC through downregulation of TGF-β expression. Like many other solid tumors, lung cancers utilize a variety of mechanisms to evade the host immune response, including downregulation of human leukocyte antigen (HLA)/major histocompatibility complex (MHC) molecules, loss or modulation of tumor antigen expression or secretion of immunosuppressive cytokines. These can at least partially explain why vaccines have not worked in lung cancer. Sequencing the “tumor mutanome” allows for in silico prediction of the immunogenicity of mutated peptides, which can then be used for tracking tumor-specific T-cell responses to develop a personalized vaccine.^[58] The peptide neoantigen vaccine may not be enough to induce an effective tumor-specific immune response, and a combination therapy approach may be needed. For example, the combination of checkpoint blockade and vaccine is a logical next step in cancer immunotherapy. Despite the advances with checkpoint blockade, not all patients respond, and the addition of vaccine therapy may further enhance T-cell proliferation.

Adoptive Cellular Therapy

There are currently three ACT techniques: tumor-infiltrating lymphocytes (TILs), T cell receptor-engineered T (TCR-T) cells, and chimeric antigen receptor T (CAR-T) cells [Figure 2]. TIL therapy involves the expansion of a heterogeneous population of endogenous T cells found in a harvested tumor, while CAR-T cells and TCR-Ts involve the expansion of a genetically engineered T-cell directed toward specific antigen targets.^[59] While successful application of ACT has been seen in hematologic malignancies, ACT in solid tumors, especially in lung cancer, is still in its early stages.

Figure 2.

ACT for lung cancer. ACT: Adoptive cell therapy; MHC: Major histocompatibility complex; TAA: Tumor-associated antigen.

Tumor-infiltrating lymphocyte (TIL) therapy

TILs are a heterogeneous population of cells that are polyclonal and have the capability to recognize various tumor antigens. The utility of autologous TIL therapy as an effective anti-cancer treatment was first reported in metastatic melanoma patients by Rosenberg and colleagues in 1988.^[60] The most encouraging clinical trials to date were conducted in patients with malignant melanoma, a tumor that shows a good response to immune therapy.^{[61,62,63,64,65]} For example, patients with metastatic melanoma who received autologous TILs can yield durable, complete responses.^[62] The overall response (OR) rates and complete response (CR) rates for these patients were 40–50% and 20%, respectively.^[62] Specifically, patients who achieve CR have demonstrated long-term disease-free survival.^[62] In addition, for patients with advanced metastatic melanoma who progressed on multiple prior therapies, including anti-PD-1, autologous TIL therapy also yielded a 38% response rate.^[66] There is growing evidence showing that TIL therapy has led to durable remissions in subsets of patients with cervical cancer,^[67] colorectal cancer,^[68] and breast cancer.^[69]

The success of TIL therapy is driven by neoantigen-directed T cells and the number of neoantigens that are targeted. The tumor mutational load and predicted neoantigen load have been shown to correlate with clinical outcomes for TIL therapies as well as PD-1 inhibitors.^[70] The fact that metastatic lung cancer is responsive to PD-1/PD-L1 immunotherapy and possesses a high mutational burden makes it an ideal candidate for ACT with TILs. However, there have been limited published studies of TIL therapies in the treatment of NSCLC. The first randomized clinical trial assessing the efficacy of TIL therapy for NCSLC was reported in 1994.^[71] Patients who received TILs had significantly longer survival than those who underwent standard treatment (median survival 22.4 months vs. 14.1 months).^[71] This study was the initial proof that TIL therapy can be applied successfully to patients with late-stage lung cancer. In a recent Phase I single-arm clinical trial, Creelan et al^[72] tested the safety and efficacy of TILs in anti-PD-1 resistant metastatic lung cancer patients. Twenty patients with metastatic NSCLC were enrolled and underwent harvesting of TILs before the initiation of ICB treatment; 16 patients subsequently received a TIL infusion and a high dose of IL-2, followed by maintenance nivolumab.^[72] The patients received a lymphocyte-depleting chemotherapy regimen before the TIL infusion. Of 13 evaluable patients, 3 had confirmed responses, and 11 had a reduction in tumor burden, with a median best change of 35%. Two patients achieved complete responses ongoing 1.5 years later.^[72] Although this study enrolled a small group of patients, the work highlights that TIL therapy can be clinically beneficial in patients with ICB-resistant NSCLC, inducing durable complete responses in some patients. More recently, a prospective, open-label, multi-cohort, non-randomized, multicenter Phase II study was started to evaluate autologous TIL therapy in patients with solid tumors (NCT03645928). Cohort 3B investigated TIL monotherapy in patients with advanced or metastatic NSCLC, who had been treated with 1–3 prior lines of systemic therapy, including either ICI or oncogene-directed therapy. Of 28 patients who received TIL therapy, the objective response rate (ORR) was 21.4% (6/28).^[73] Among them, one patient had a complete metabolic response (defined as the visual absence of pathological fluorodeoxyglucose uptake in all baseline lesions identified on the baseline positron emission tomography [PET] scan), and 2 responses occurred in patients who were PD-L1 negative.^[73] All responders received ≥2 prior lines of systemic therapy.^[73] This study demonstrated that TILs could be a treatment option in NSCLC patients who had previously received ICIs. Other ongoing clinical trials of TILs in NSCLC are summarized in Table 1.

Table 1.

Selected clinical trials of TIL therapy in lung cancer.

NCT No.	Title	Phase	Types of cancer	Status
NCT03215810	Nivolumab and tumor infiltrating lymphocytes (TIL) in advanced non-small cell lung cancer	I	Stage IV or recurrent NSCLC	Completed
NCT05681780	Clinical trial of CD40L-augmented TIL for patients with EGFR, ALK, ROS1 or HER2-driven NSCLC	I/II	Stage IV or recurrent NSCLC	Recruiting
NCT05878028	L-TIL plus tislelizumab for PD1 antibody resistant aNSCLC	II	Stage IV NSCLC	Recruiting
NCT04614103	Autologous LN-145 in patients with metastatic non-small-cell lung cancer	II	Metastatic stage IV NSCLC	Recruiting
NCT03419559	Study of autologous tumor infiltrating lymphocytes (LN-145) in combination with durvalumab in non-small cell lung cancer	II	Stage III or stage IV NSCLC	Withdrawn
NCT03645928	Study of autologous tumor infiltrating lymphocytes in patients with solid tumors	II	Unresectable or metastatic melanoma, advanced, recurrent or metastatic HNSCC, stage III or stage IV NSCLC	Recruiting
NCT05566223	CISH inactivated TILs in the treatment of NSCLC (CheckCell-2)	I/II	PD-L1 negative or positive metastatic NSCLC	Not yet recruiting
NCT05573035	A study to investigate LYL845 in adults with solid tumors	I	Melanoma, NSCLC, CRC	Recruiting
NCT05576077	A study of TBio-4101 (TIL) and pembrolizumab in patients with advanced solid tumors (STARLING)	I	Advanced or metastatic breast carcinoma, colorectal adenocarcinoma, uveal melanoma, cutaneous melanoma, NSCLC, HNSCC	Recruiting
NCT02133196	T cell receptor immunotherapy for patients with metastatic non-small cell lung cancer	II	stage IV or unresectable NSCLC	Recruiting
NCT03903887	A study of anti-PD1 antibody-activated TILs in non-small cell lung cancer	I/II	Stages II–IIIA NSCLC	Unknown status
NCT05361174	A Study to investigate the efficacy and safety of an infusion of IOV-4001 in adult participants with unresectable or metastatic melanoma or stage III or IV non-small-cell lung cancer	I/II	Unresectable or metastatic melanoma or stage III or IV NSCLC	Recruiting
NCT01820754	Evaluation of circulating T cells and tumor infiltrating lymphocytes (TILs) during/after pre-surgery chemotherapy in NSCLC	II	Stages 1B, 2, or 3 NSCLC	Completed

ALK: Anaplastic lymphoma kinase; aNSCLC: Advanced non-small cell lung cancer (NSCLC); CISH: Cytokine inducible SH2 containing protein; CRC: Colorectal cancer; EGFR: Epidermal growth factor receptor; HER2: Human epidermal growth factor receptor 2; HNSCC: Head and neck squamous cell carcinoma; L-TIL: Liquid tumor infiltrating lymphocytes; PD1: Programmed cell death 1; ROS1: ROS proto-oncogene 1, receptor tyrosine kinase; TIL: Tumor infiltrating lymphocyte.

TIL immunotherapy involves several laboratory and clinical steps, which start with surgical resection of tumor tissue from the patients and continue with tumor processing to establish T cell cultures, which are then expanded in IL-2-containing media. In 2017, Ben-Avi et al^[74] optimized the expansion method of lung cancer-derived TILs under a good manufacturing practice (GMP) environment. After isolation from the tumor tissue, the TILs were expanded with anti-CD3 antibody, IL-2, and irradiated peripheral blood mononuclear cells from non-related donor cells in G-Rex flasks. This method can yield up to 5 × 10¹⁰ functional TILs for infusion starting from 1 × 10⁶ live nucleated cells isolated from a single lung tumor piece. This study indicates that TILs from lung cancer patients can be expanded to treatment levels under GMP conditions.

TIL may hold some distinguishing advantages for treating solid tumors. Firstly, TILs have diverse TCR clonality, are capable of recognizing an array of tumor antigens, and therefore may be superior in tackling tumor heterogeneity compared to other ACT approaches, such as CAR-T and TCR-T cell therapy. In line with this, TIL has demonstrated better clinical efficacy than CAR-T in solid tumors containing high mutation load, such as melanoma.^[75] In addition, off-target toxicity has seldom been reported in TIL therapy, probably due to the negative selection of TCRs of TIL during the early development of T cell immunity. On the contrary, the engineered tumor-targeting single-chain variable fragments (scFv) in CAR-T or affinity-enhanced TCR in TCR-T products may lead to toxicity if they bear cross-reactivity with antigens on normal tissues. However, TIL therapy also has some disadvantages. Currently, the most widely used TIL production method is to isolate infiltrating lymphocytes from tumor tissues and then culture and expand these cells in vitro. The administration of high-dose IL-2 used as a standard of care to support the growth and activity of infused TIL, however, may restrain the clinical application of TIL therapy. High-dose IL-2 could induce systemic toxicity,^[76] and could also promote regulatory T cells that suppress the anti-tumor response of TIL.^[77] Furthermore, the short-term persistence of autologous mature TILs in vivo is also a challenge to achieve the maximal outcome of TIL therapy.^[78]

T cell receptor–engineered T cell therapy

The TCR is a molecule on the surface of T cells that specifically recognizes and mediates immune responses and consists of two highly variable heterogeneous peptide chains linked by disulfide bonds.^[79] TCR-T cells are constructed by transferring a TCR gene sequence that specifically recognizes tumor antigens into T cells through genetic engineering so that the T cells have the ability to specifically kill tumor cells.^[80] TCR-T cells can recognize not only specific antigens on the surface of tumor cells, but also intracellular antigens presented by specific MHC molecules, which allows TCR-T cells to recognize a wider spectrum of target antigens and may improve tumor cell detection and killing while improving T cell persistence.^[80,81] Moreover, because TCR T-cell therapy utilizes peripheral lymphocytes, this represents an advantage over TIL therapy.^[80] Currently, TCR-T cells targeting TAAs or tumor-specific antigens (TSAs), such as carcinoembryonic antigen (CEA), glycoprotein 100 (gp100), melanoma-associated antigens (MAGEs), melanoma antigen recognized by T cells 1 (MART-1), New York esophageal squamous cell carcinoma-1 (NY-ESO-1), and malignant peripheral nerve sheath tumors (MPNST), showed promising results in clinical trials in multiple cancer types, including melanoma, colorectal cancer, synovial sarcoma, and esophageal cancer.^[81]

To date, only two clinical trials of TCR-T therapy in NSCLC have been reported. In a Phase 1 trial, four patients with metastatic NSCLC (mNSCLC) were enrolled (NCT02457650) and were aimed to evaluate the safety and feasibility of NY-ESO-1 TCR-T cell therapy for HLA-A2-positive patients.^[82] NY-ESO-1 is expressed in approximately 11.8–21% of NSCLCs.^[83,84] The results showed that NY-ESO-1 TCR-T cells in four HLA-A2-positive patients with NSCLC are well tolerated without evident severe toxicities. Two patients had clinical responses to NY-ESO-1 TCR-T cell therapy, including one who achieved a short-term partial response for 4 months.^[82] Another Phase I clinical trial evaluated the safety and efficacy of MAGE-A10-specific TCR-T cells in patients with MAGE-A10⁺ advanced NSCLC.^[85] Among the 11 treated patients, one had a partial response, four reported stable disease, five had clinical or radiographic progressive disease, and one was not evaluable. MAGE-A10-TCR T cells demonstrated an acceptable safety profile and no evidence of toxicity related to off-target binding or alloreactivity.^[85] Other clinical trials are currently ongoing to determine the feasibility, safety, and efficacy of this personalized therapy in NSCLC [Table 2].

Table 2.

Selected clinical trials of TCR T cell therapy in lung cancer.

NCT No.	Title	Phases	Types of cancer	Status
NCT03778814	T cell receptor (TCR)-engineered T (TCR-T) cell immunotherapy of lung cancer and other solid tumors	I	Advanced lung tumor or other solid tumor	Recruiting
NCT02592577	MAGE A10c796T for advanced NSCLC	I	Stage IIIb or stage IV NSCLC	Completed
NCT05194735	Phases I/II study of autologous T cells to express TCRs in subjects with solid tumors	I/II	Gynecologic cancer, colorectal cancer, pancreatic cancer, NSCLC, cholangiocarcinoma	Not recruiting
NCT02588612	Letetresgene autoleucel engineered T cells in NY-ESO-1 positive advanced non-small cell lung cancer (NSCLC)	I	Stage IIIb or stage IV NSCLC	Completed
NCT03412877	Administration of autologous T-cells genetically engineered to express T-cell receptors reactive against neoantigens in people with metastatic cancer	II	Metastatic NSCLC and other solid tumors	Recruiting
NCT04639245	Genetically engineered cells (MAGE-A1-specific T cell receptor-transduced autologous T-cells) and atezolizumab for the treatment of metastatic triple negative breast cancer, urothelial cancer, or NSCLC	I/II	MAGEA1 positive TNBC, urothelial carcinoma, or NSCLC	Terminated due to slow accrual
NCT06043713	Autologous CD8+ and CD4+ transgenic T cells expressing high-affinity KRAS G12V mutation-specific T cell receptors (FH-A11KRASG12V-TCR) in treating patients with metastatic pancreatic, colorectal and non-small cell lung cancers with KRAS G12V mutations	I	Metastatic pancreatic, colorectal and NSCLC with KRAS G12V mutations	Not yet recruiting
NCT03132922	MAGE-A4c1032T for multi-tumor	I	MAGE-A4 positive solid tumors	Not recruiting
NCT01967823	T cell receptor immunotherapy targeting NY-ESO-1 for patients with NY-ESO-1 expressing cancer	II	NY-ESO-1-expressing cancer	Completed
NCT05296564	Anti-NY-ESO-1 TCR-gene engineered lymphocytes given by infusion to patients with NY-ESO-1-expressing metastatic cancers	I/II	NY-ESO-1-expressing metastatic cancers	Recruiting

MAGE: Melanoma-associated antigen; MAGEA: Melanoma associated antigen family A; NY-ESO-1: New York esophageal squamous cell carcinoma-1; TNBC: Triple-negative breast cancer.

Chimeric antigen receptor (CAR)-T cell therapy

TCR-T and CAR-T cell therapies involve genetically engineered T cells modified to express a receptor directed against a tumor antigen. TCR-T cell therapy offers several advantages in solid tumors, as discussed above. However, the antigen recognition for TCR-T cells is restricted to the human leucocyte antigen (HLA) allele presenting the epitope, thus restricting the number of patients who can benefit from a given TCR-T cell therapy. CAR-T cells have gained a lot of attention due to their breakthrough results in hematological malignancies,^[86] with six therapies now FDA-approved, targeting CD19 or B cell maturation antigen (BCMA). However, the clinical application of CAR-T cells is still limited and unsatisfactory when targeting lung cancer.

The first step in successful CAR T cell therapy is to select the optimal surface antigen. Several ideal antigenic targets have been identified for lung cancer cell therapy and are being tested in clinical trials, including EGFR, mesothelin (MSLN), MUC1, inactive tyrosine-protein kinase transmembrane receptor (ROR1), CEA, HER2, PD-L1, and B7-H3.^[87] To date, only a few CAR-T clinical trials in NSCLC patients have reported preliminary results, describing modest clinical trials.

Two Phase I clinical trials demonstrated the safety of EGFR-specific CAR-T cells in EGFR-overexpressing relapsed/refractory mNSCLC. In the first Phase I clinical study (NCT01869166), the EGFR-targeted CAR-T cell infusions were well-tolerated without severe toxicity.^[88] Of 11 evaluable patients, two patients obtained partial response and five had stable disease for two to eight months.^[88] In the second trial (NCT03182816), EGFR CAR T cells were generated by the non-viral piggyBac transposon system, a simpler, more economical, and alternative way to introduce CAR transgenes into T cells. Of 9 patients who received two cycles of piggyBac-generated EGFR-CAR T cell therapy, one patient achieved a partial response which persisted for more than one year, while six had stable disease, and two had progressed disease.^[89] The PFS of these nine patients was 7.13 months (95% CI: 2.71–17.10 months), while the median OS was 15.63 months (95% CI: 8.82–22.03 months).^[89] These two trials demonstrated that EGFR-CAR T-cell therapy is feasible and safe in the treatment of EGFR-positive NSCLC patients.

The TAA MSLN is an attractive target for NSCLC,^[90] and its overexpression is strongly associated with tumor aggressiveness.^[90] MSLN-targeted CAR T cells are being tested in preclinical and clinical studies. Recently, a single-center, phase I study (NCT02414269) reported the results of regionally delivered, autologous MSLN-targeted CAR T-cell therapy in mesothelioma, metastatic lung cancer, and metastatic breast cancer.^[91] The results showed that regional administration of CARs was safe and well-tolerated. The median OS of patients receiving CAR T-cell infusion was 23.9 months (83% 1-year OS rate). Eight patients had a stable condition for ≥ 6 months; two patients showed complete metabolic responses on PET scan.^[91] Another Phase I/II clinical study is being conducted to assess the safety and efficacy of anti-MUC1 CAR-T cells combined with PD-1 knockout in treating patients with advanced NSCLC (NCT03525782). Their published report showed that, of the 20 assessed patients, 11 presented with stable disease while 9 had progressive disease.^[92] All patients had significant symptom improvements after infusion,^[92] suggesting that with PD-1 disruption, anti-MUC1 CAR cells are safe and well tolerated in NSCLC patients. According to the information from the website of the Clinical Trials (https://www.clinicaltrials.gov), more CAR T-cell therapy approaches are under investigation in Phase I or II clinical trials for lung cancer, which are summarized in Table 3.

Table 3.

Selected clinical trials of CAR T cell therapy in lung cancer.

NCT No.	Phases	Targets	Application	Study start	Status
NCT01869166	1, 2	EGFR	CAR T cells	2013	Unknown
NCT04153799	1	EGFR	CXCR5 modified EGFR chimeric antigen receptor autologous T cells	2019	Unknown status
NCT02414269	1, 2	Mesothelin	Autologous T cells genetically engineered to target mesothelin	2015	Active, not recruiting
NCT02580747	1	Mesothelin	CAR T-meso	2015	Unknown status
NCT02587689	1, 2	Mucin-1	Anti-MUC1 CAR T Cells	2015	Unknown status
NCT03525782	1, 2	Mucin-1	Anti-MUC1 and PD-1 knockout CAR T Cells	2018	Unknown status
NCT03356808	1, 2	Multiple antigens	CAR T cells	2017	Unknown status
NCT03198052	1	Multiple antigens	CAR T cells	2017	Recruiting
NCT04842812	1	PD-1 and CTLA-4	CAR T cells	2021	Recruiting
NCT02706392	1	ROR1	CAR T cells	2016	Terminated
NCT02349724	1	CEA	CAR T cells	2014	Unknown status
NCT04348643	1, 2	CEA	CAR T cells	2020	Recruiting
NCT03198052	1	Multiple antigens	CAR T cells	2017	Recruiting
NCT01935843	1, 2	HER2	CAR T cells	2013	Unknown status
NCT02713984	1, 2	HER2	CAR T cells	2016	Withdrawn
NCT03740256	1	HER2	Oncolytic adenovirus and CAR T cells	2020	Recruiting
NCT04660929	1	HER2	Adenovirally transduced autologous macrophages	2021	Recruiting
NCT03060343	Early phase 1	PD-L1 and CD80/CD86	Zeushield cytotoxic T lymphocytes	2016	Unknown status
NCT03330834	1	PD-L1	CAR T cells	2017	Terminated
NCT03525782	1, 2	MUC1	PD-1 knock out CAR T cells	2018	Unknown status
NCT04864821	Early phase 1	CD276	CAR T cells	2021	Unknown status
NCT03198052	1	Multiple antigens	CAR T cells	2017	Recruiting

CAR T: Chimeric antigen receptor T cell; CEA: Carcinoembryonic antigen; CTLA-4: Cytotoxic T-lymphocyte-associated antigen 4; CXCR5: C-X-C chemokine receptor type 5; EGFR: Epidermal growth factor receptor; HER2: Human epidermal growth factor receptor 2; MUC1: Mucin1; PD-1: Programmed cell death-1; PD-L1: Programmed cell death-1 ligand-1; ROR1: Inactive tyrosine-protein kinase transmembrane receptor.

SCLC accounts for about 15% of lung and is marked by high metastasis and poor prognosis, with a median overall survival of approximately 13 months.^[93,94] Currently, chemotherapy remains the standard treatment for first- and second-line management of SCLC. CAR T cell therapy also shows promising results in SCLC. Delta-like ligand 3 (DLL3) is an inhibitory ligand of Notch receptors, which is expressed in most SCLC tumors but minimally expressed in normal tissues,^[95] suggesting that it may be a promising target for cancer immunotherapy. A first Phase 1 study of CAR T cell therapy targeting DLL3 was conducted in patients with relapsed/refractory SCLC (NCT03392064). Five patients received at least 1 intravenous infusion of DLL3-targeted CAR T cells.^[96] No dose-limiting toxicities or grade 4/5 treatment-related adverse events (TRAE) were observed.^[96] Of 4 evaluable patients, one achieved PR, two had SD, and one had PD. Median PFS was 3.7 months (range, 1.1–6.7 months) and median OS was 7.4 months (range, 4.6–18.9 months).^[96] This first trial suggests that CAR-T cell therapy for SCLC is safe and has promising anti-tumor activity.

Current Obstacles of ACT for Lung Cancer

Challenges in treating solid tumors, especially lung cancer, include the identification of a specific target that is highly homogenous and stably expressed in the tumor rather than healthy tissue. A major reason for failure is the insufficient load of mutated tumor antigens. Cancer vaccines are likely ineffective due to poor tumor-antigen presentation of the lysed tumor cells. Furthermore, off-tumor effects occur due to poor specificity and excessive activation of immune cells, especially T cells, leading to severe toxic side effects. There are further challenges associated with ACT, including the physical and immune barriers associated with its applications. In this section, we will discuss the current challenges of ACT in treating lung cancers.

On-target, off-tumor toxicity

TAAs are relatively restricted to cancer cells while limited to normal tissues. Lung cancer is characterized by large heterogeneity, in particular, the cellular composition, chromosomal structure, developmental trajectory, intercellular signaling networks, and phenotype dominance.^[11] Intratumoral heterogeneity is influenced by many factors, such as the progression of the tumor, mutational burden, and unique genetic profile. Quantification of the intratumor heterogeneity showed lung squamous carcinoma has higher inter- and intratumor heterogeneity than lung adenocarcinoma. The advanced NSCLC microenvironment reveals a rich program of stromal and immune components.^[97]

The main issue with cell therapy for lung cancer is the lack of an ideal target antigen. The success of candidate target antigens is contingent upon their safety and the degree of on-target/off-tumor toxicity. The off-tumor toxicity of TCR-T or CAR-T cells results in organ dysfunction, such as pulmonary fibrosis, liver damage, and gastrointestinal disorders. In addition, cross-reactivities have been reported in clinical trials using affinity-enhanced TCR-T cells.^[98,99] To address the issue of off-tumor toxicity and TAA heterogeneity, a variety of techniques have been employed, including targeting mutated tumor-specific antigens, targeting multiple tumor target antigens, dual CAR system, and suicide genes, etc. New sequencing technologies may also reveal more accurate target antigen expression profiles for TAA selection and better prediction of the efficacy and toxicity of novel cell therapies. Furthermore, designing CAR constructs targeting multi-targets, using lower affinity scFv, or continuing the search for safer TAAs may also be effective strategies in future lung cancer treatments.

Cytokine release syndrome and neurotoxicity

Cytokine release syndrome (CRS) is a severe life-threatening cytokine-associated toxicity that frequently develops following ACT, in which rare cases present with prolonged fever, chills, muscle pain, cardiogenic shock, and disseminated intravascular coagulation. While CRS is rarely reported with the use of ICIs, severe CRS was reported when atezolizumab or nivolumab plus ipilimumab was administered along with or after chemotherapy, respectively.^[100,101] Clinical studies show that CRS is mainly caused by activated CAR-T cells with a significant increase in inflammatory IL-6, inteferon-γ (IFN-γ), and tumor necrosis factor-α (TNF-α) cytokines released by immune cells disrupting the balance between pro-inflammatory and anti-inflammatory responses. A controlled “switch” for CAR-T cells is effective in reducing pro-inflammatory cytokine secretion and clearing CAR-T cells from the body prior to system toxicity.^[102] For example, herpes simplex virus thymidine kinase (HSV-TK), human inducible caspase 9 (iCasp9), mutant human thymidylate kinase (mTMPK), and human CD20 can be expressed in donor T cells and have been shown to kill transduced CAR-T cells during adverse events in the early clinical trials of immunotherapy.^[103] The use of the FDA-approved tyrosine kinase inhibitor, dasatinib, also acts as a CAR-T cell “switch” to suppress T-cell activation by inhibiting TCR signaling kinases, and the inhibitor has been shown to protect mice models from CRS.^[104] In addition, previous studies have demonstrated that regulating the in vivo lifespan and kinetics of CAR-T cells by optimizing CAR gene transfection and using nanoparticles^[105] can reduce and avoid CRS. Therefore, avoiding CRS damage after CAR-T cell immunotherapy will be a key issue to address and focus on in the treatment of lung cancer in the future. CRS is commonly observed after CAR-T, and the anti-IL-6 receptor monoclonal antibody tocilizumab has shown efficacy for severe CRS.

Neurotoxicity, also known as immune effector cell-associated neurotoxicity (ICANS) or CAR-T cell-related encephalopathy syndrome (CRES), is characterized by various neurological symptoms such as headache, aphasia, and delirium, even cerebral hemorrhage, seizures, and death. CRS may contribute to the risk of complications CRES following the disruption of the blood-brain barrier, allowing immune effector cells and inflammatory mediators to infiltrate into the central nervous system, leading to neurotoxicity. CRES is reversible with tocilizumab and dexamethasone treatment. Corticosteroid usage is another effective management strategy of CAR-T cell therapy that needs to be explored in lung cancer patients. Overall, improving our understanding of the pathology of CRES associated with adoptive cell therapy for lung cancer patients is greatly warranted. The structure of CARs is continuously evolving to enhance the efficacy and limit the toxic side effects in the clinic.^[106]

Immunosuppressive tumor microenvironment

ACT efficacy is also limited in lung cancer patients because of the immunosuppressive TME, which is characterized by hypoxia, immunosuppressive signaling by cellular immune checkpoint receptors, oxidative stress, tumor-derived cytokine suppression, etc. Tumor cells can release a variety of immunosuppressive factors, including vascular endothelial growth factor (VEGF), IL-4, IL-10, TGF-β, and prostaglandin E2, leading to the activation of suppressive immune cells such as regulatory T cells, myeloid-derived suppressor cells, and tumor-associated macrophages to further contribute to the immunosuppressive environment. ACT combined with ICIs is one of the most promising strategies with a strong scientific rationale that the adoptively transferred T cells in the TME are compromised by the expression of suppressive immune checkpoints. In addition, T cells can also be engineered to have cell-intrinsic checkpoint blockade to obtain the same results. For example, MSLN-CAR T cells overexpressing PD-1 dominant negative receptor are being preclinically tested in lung cancer patients.^[107] Therefore, ACT co-expressing immune-related factors may be an effective strategy for the clinical treatment of lung cancer.

Future Directions

Although recent advancements in treatment options have improved clinical outcomes, lung cancer remains the leading cause of cancer-related deaths. Improving our understanding of the complex interactions between tumor cells and the surrounding host immune cells of the tumor microenvironment has led to the development of novel therapeutic strategies, including immune checkpoint inhibitors. Further research is required to gain a deeper understanding of the lung tumor microenvironment with the aim of overcoming the major challenges in immunosuppression and immunoediting. While CAR-T cell therapy holds great promise for lung cancer immunotherapy, there are drawbacks associated with its use, including CRS, neurotoxicity, antigen escape, and long-term durable responses. As a component of the innate immune system, NK cells are capable of directly recognizing and killing tumor cells, and it is likely that the next wave of novel treatment options for lung cancer will include NK cell-based immunotherapy approaches.^[108] The use of NK cells offers several advantages, including their innate ability to target cancer cells without prior activation, their potential to recognize a broad range of tumor cell types, and low risk of causing graft versus host disease (GVHD) compared to other cell-based therapies. Moreover, NK cells traffic into the lung, which is one of the main places where NK cells reside, and the lack of GVHD justifies patients can be timely treated with allogeneic, affordable NK cell products with repeated doses.^[108] An allogeneic “off-the-shelf” product can potentially cost significantly less to manufacture compared to autologous CAR T cell products currently on the market. There is a substantial need for safe treatment options that will not create an economic burden. Engineered NK cells are showing great promise in preclinical settings.^[109,110] Investigators are addressing the challenges of NK cell source, manufacturing, and in vivo persistence for optimal clinical efficacy. Importantly, like many other cancers, relapsed lung cancer is aggressive and very complicated. Thus, targeting multiple mechanisms in both tumor cells and/or immune cells with different agents should be a direction to follow.

Concluding Remarks

Lung cancer typically presents at an advanced stage where a cure is not possible with the currently available therapeutic strategies. Clinical trials are being conducted on prevention and treatment options to meet some of the unmet needs for lung cancer treatment. The use of small-molecule tyrosine kinase inhibitors and/or immunotherapy has led to unprecedented survival benefits in select patients. Adoptive cell therapy is expected to be a pivotal one in the lung cancer therapy arsenal in the future.

Conflicts of interest

None.